JP6506162B2 - Micro needle sheet - Google Patents

Description

  One aspect of the present invention relates to a microneedle sheet used to assist administration of an active ingredient by the microneedle.

  Conventionally, a microneedle for administering an active ingredient through the skin, and a device comprising the microneedle are known. For example, the rotatable microstructure device described in Patent Document 1 below comprises a curved substrate and a roller structure comprising a plurality of microelements affixed onto a first surface of the substrate. ing. The plurality of microelements have a predetermined size and shape so as to penetrate the stratum corneum of the skin when the microstructured device is placed on the skin and rolled in a predetermined direction.

Japanese Patent Application Publication No. 2005-503210 International Publication No. 2013/187392

  However, in the microstructure device described in Patent Document 1 above, since the microelements are exposed on the roller, the needle is required to be removed before applying the active ingredient to the skin via the microneedle It may hit or get caught on the user's skin, clothes, etc.). Therefore, there is a demand for securing the safety of the microneedle in handling.

  In order to solve this problem, according to Patent Document 2, a plurality of microneedles formed on the sheet substantially along the main surface of the sheet is provided, and the microneedles are raised from the main surface by the bending of the sheet. A microneedle sheet has been proposed in which the microneedles pierce the skin. In such a microneedle sheet, the microneedles are substantially along the major surface of the sheet until the sheet is bent. This means that the tip of the microneedle does not protrude from the main surface until the microneedle is applied to the skin. Therefore, unless the microneedle sheet is applied to the skin, there is no concern that the microneedles will hit or get caught on other things. As a result, the safety in handling the microneedle can be secured. Here, such a microneedle sheet is required to have the property that the microneedle is easily stuck in the skin, that is, the puncturing property.

The microneedle sheet according to one aspect of the present invention includes a plurality of microneedles formed on the sheet substantially along the main surface of the sheet, and is measured according to the slide method defined in JIS L 1096: 2010. The descent distance of the sheet is 4.5 cm to 12.9 cm, the material of the sheet is metal, and the microneedle rises from the main surface when the sheet is bent. The microneedles that stand up pierce the skin.

  In such aspects, the microneedle sheet exhibits excellent puncture properties.

  According to one aspect of the present invention, safety during handling of the microneedle can be secured, and excellent puncture performance is exhibited.

It is a top view of the microneedle sheet concerning an embodiment.

In the present specification, the descent distance means a descent distance measured in accordance with the 8.21.2B method (slide method) defined in JIS L 1096: 2010. That is, after the upper surface of the slide type testing machine main body and the moving table coincide with the lowering distance , a test piece (microneedle sheet) of 5 mm × 150 mm is installed, and the end 2 cm of the test piece is a weight , And gently turn the handle to lower the carriage, meaning the lowering distance (cm) when the free end of the test piece is separated from the carriage.

  In the present specification, the three-point bending load value means a three-point bending load value measured in accordance with the method defined in JIS K 7171: 2008. That is, with the three-point bending load value, test specimens (microneedles / sheets) of 5 mm x 30 mm are symmetrically installed on the left and right supports (radius of indenter: 0.5 mm, distance between fulcrums: 5 mm) Lower the indenter at the test speed of 1 mm / sec to the center between the fulcrums of the test piece, and while the test piece is bent until it reaches a predetermined deflection state (the position where the indenter touches the test piece 5 mm) The load value (N) is meant.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings.

  The structure of the microneedle sheet 10 according to the embodiment will be described with reference to FIG. The microneedle sheet 10 is a device for administering any active ingredient (for example, drug) in vivo, and has a large number of microneedles to be pierced on the skin.

  As shown in FIG. 1, the microneedle sheet 10 is strip-shaped and has a plurality of microneedles 12 formed on the sheet substantially along the major surface 11 of the sheet. The microneedles 12 are aligned in the longitudinal and width directions of the sheet, and the tips of all the microneedles 12 face the end of the sheet (leftward in FIG. 1) without exception.

The lowering distance of the microneedle sheet is 4.5 cm to 12.9 cm. When the descent distance is within the above range, the microneedle sheet exhibits excellent puncture properties. From the viewpoint of unwindability after puncturing, the lowering distance of the microneedle sheet may be 6.2 cm to 12.9 cm.

  The three-point bending load value of the microneedle sheet may be 0.008 N to 3.02 N. When the three-point bending load value is within the above range, the microneedle sheet tends to exhibit excellent flexibility.

  The material of the microneedle sheet 10 and the microneedle 12 is metal. The metal is not particularly limited as long as it can form the microneedle sheet 10 and the microneedle 12. Specifically, for example, iron, chromium, nickel, molybdenum, titanium, aluminum, vanadium, palladium, ruthenium, tantalum , Cobalt, niobium, zirconium, noble metals (gold, silver, copper, platinum etc.), alkali metals (sodium, potassium etc.), alkaline earth metals (magnesium, calcium etc.), and alloys of these (stainless steel, titanium alloys etc.) Can be mentioned.

  As stainless steel, for example, SUS304s containing 18% to 20% of chromium and 8% to 10.5% of nickel relative to the total amount of stainless steel (Specific example: SUS304, SUS304Cu, SUS304L, SUS304N1, SUS304N2, SUS304LN SUS316 series containing 16% to 18% chromium, 10% to 14% nickel, and 2% to 3% molybdenum (specific examples: SUS316, SUS316L, SUS316LN, SUS316Ti, SUS316Ti, SUS316J1, SUS316J1L) Etc.).

  Examples of titanium include, for example, JIS Standard 1, 2, 3, and 4 titanium.

  As a titanium alloy, for example, a titanium alloy according to JIS standard 60 containing 5.5% to 6.75% of aluminum and 3.5% to 4.5% of vanadium based on the total weight of the titanium alloy, the total weight of the titanium alloy Against 60% of aluminum and 5.5% to 4.5% of vanadium containing titanium alloy according to JIS Standard 60 E, 2.5% of aluminum to the total weight of the titanium alloy The titanium alloy of 61 types of JIS specification etc. which contain -3.5% and 2.0% -3.0% of vanadium are mentioned.

  As the metal, SUS304, SUS316L, titanium, and a titanium alloy are preferable from the viewpoint of biocompatibility of the microneedle sheet, mobility of the bent portion, ease of bending, and puncture property.

  The microneedles 12 can be formed by laser, etching or the like. As shown in FIG. 1, in the present embodiment, the microneedles 12 have a triangular shape, but the shape of the microneedles is not limited at all. Since it is not necessary to raise the microneedles 12 in advance from the major surface 11 of the sheet, the microneedle sheet 10 can be manufactured easily and inexpensively.

  The thickness of the microneedle sheet 10 is also not limited. Specifically, the lower limit of the thickness of the microneedle sheet 10 may be 5 μm or 20 μm, and the upper limit of the thickness may be 1000 μm, 300 μm, 70 μm or 50 μm. The lower limit of the thickness of the microneedle sheet 10 is determined in consideration of the strength of the microneedle 12 which punctures the skin, and the upper limit of the thickness is determined in consideration of the flexibility of the sheet, the punctability of the microneedle 12, etc. Be

  In the microneedle sheet according to one aspect of the present invention, the thickness of the sheet may be 5 μm to 70 μm. By setting the thickness in this manner, the puncturing property of the microneedle sheet becomes excellent. In addition, since the microneedle sheet becomes thin and flexible by setting the thickness in this way, the sheet can be applied to the skin according to the shape of the living body, and as a result, the active ingredient is efficiently administered. can do.

  The length and width of the microneedle sheet 10 are also not limited. Specifically, the lower limit of the length of the microneedle sheet 10 may be 0.1 cm or 1 cm, and the upper limit of the length may be 50 cm or 20 cm. The lower limit of the width of the microneedle sheet 10 may be 0.1 cm or 1 cm, and the upper limit of the width may be 60 cm or 30 cm. The lower limit of the length and width of the microneedle sheet 10 is determined in consideration of the dose of the active ingredient, and the upper limit of the length and width is determined in consideration of the size of the living body.

The parameters for the microneedles 12 are also not limited. Specifically, the lower limit of the length of the microneedle 12 may be 10 μm or 100 μm, and the upper limit of the length may be 10000 μm or 1000 μm. Here, the length of the microneedle 12 is the distance from the bottom of the microneedle 12 (the portion of the root rising from the major surface 11) to the top. The lower limit of the density of the needles may be 0.05 needle / cm ² or 1 needle / cm ² , and the upper limit of the density may be 10000 needles / cm ² or 5,000 needles / cm ² . The lower limit of density is a value converted from the number and area of needles capable of administering 1 mg of the active ingredient, and the upper limit of density is a limit value in consideration of the shape of the needle.

  As shown in FIG. 1, in the present embodiment, the microneedles 12 have a triangular shape, but the shape of the microneedles is not limited at all. Further, as shown in FIG. 1, in the present embodiment, the microneedles 12 are uniform in size, orientation, and distribution in the microneedle sheet, but they need not be uniform. When the microneedle 12 has a triangular shape, the angle of the tip thereof may be 10 ° or more, 20 ° or more, 150 ° or less, or 120 ° or less.

  As a method of preparing an active ingredient to be applied to the skin, a method of coating the microneedle sheet 10 itself with the active ingredient in advance, a method of adding a layer containing the active ingredient to the upper layer of the microneedle sheet 10, and The method of applying the active ingredient on the skin before puncturing the needle 12 into the skin and the method of applying the active ingredient on the skin of the microneedle 12 after puncturing the skin can be considered. If the microneedle sheet 10 is previously coated with an active ingredient, it is preferable to apply a coating solution of a predetermined viscosity to the entire sheet with a uniform thickness as much as possible, but since the microneedles 12 are along the major surface 11 Such application can be facilitated. The coating may be performed using the principle of screen printing or may be performed by other methods.

  When applying the microneedle sheet 10 to the skin, an applicator can be used. Known applicators are available, for example the applicators described in WO 2014/203911.

  As described above, the microneedle sheet according to one aspect of the present invention includes a plurality of microneedles formed on the sheet substantially along the main surface of the sheet, and the microneedles are mainly formed by bending the sheet. Standing up from the surface, the microneedles that stand up pierce the skin.

  In such a side surface, the microneedles are substantially along the main surface of the sheet until the sheet is bent. This means that the tip of the microneedle does not protrude from the main surface until the microneedle is applied to the skin. Therefore, unless the microneedle sheet is applied to the skin, there is no concern that the microneedles will hit or get caught on other things. As a result, the safety in handling the microneedle can be secured. For example, the user can safely perform storage, transport, preparation immediately before use, etc. of the microneedle / sheet.

  Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited thereto.

[Test Example 1: Measurement of Three-Point Bending Load Value and Falling Distance , and Evaluation of Prickability]
(Preparation of microneedle sheet)
The following four patterns of microneedles with different arrangement densities for five types of SUS304 foils with thicknesses of 5 μm, 10 μm, 20 μm, 50 μm and 70 μm:
D94 (length: 500 μm, width: 220 μm, placement density: 100 pcs / cm ² )
D35 (Length: 500 μm, Width: 220 μm, Placement density: 225 pcs / cm ² )
D95 (length: 500 μm, width: 220 μm, placement density: 150 pcs / cm ² )
D96 (length: 500 μm, width: 220 μm, placement density: 75 pcs / cm ² )
Various microneedle sheets were produced by etching to obtain

(3 point bending test)
Measure the three-point bending load value according to the test method specified in JIS K 7171: 2008 (radius of indenter R ₁ : 0.5 mm, radius of support R ₂ : 1.4 mm, distance between supporting points L: 5 mm) did. Specifically, test pieces obtained by cutting the microneedle sheet prepared above to a size of 5 mm × 30 mm are symmetrically installed on the left and right supports, and the indenter is 1 mm / in the center between the fulcrums of the test pieces. The test load was lowered at a test speed of sec, and the maximum load value was measured while the test piece was bent to a predetermined deflection state (a position where the indenter pushed in 5 mm after contact with the test piece).

( Descent distance test)
The descent distance was measured in accordance with the 8.21.2B method (slide method) defined in JIS L 1096: 2010. Specifically, after the upper surfaces of the slide type testing machine main body and the moving table are matched, a test piece obtained by cutting the prepared microneedle sheet into 5 mm × 150 mm is installed, and the end of the test piece A 2 cm weight was fixed with a weight, and the handle was gently turned to lower the carriage, and the lowering distance (cm) when the free end of the test piece was separated from the carriage was measured.

(Evaluation of puncture ability)
The punctability of the microneedle sheet produced above was evaluated by the following evaluation method (1) or evaluation method (2). The evaluation method (1) was used when the thickness of the microneedle sheet was 10 μm or more, and the evaluation method (2) was used when the thickness of the microneedle sheet was 5 μm.

(Evaluation method of puncture ability (1))
The prepared microneedle sheet and one end of a 75 μm thick film, which was about the same size as the microneedle sheet, were fixed to each other. The microneedle sheet to which the film is fixed is disposed between a styrene copolymer elastomer sheet as a model of the skin and a flat plate having a gap of about 300 μm, and one end thereof is a styrene copolymer. It was fixed to the elastomeric sheet. The film was pulled in a horizontal direction, and the microneedle was punctured into the styrene copolymer elastomer sheet while bending the microneedle sheet by 180 °. In addition, the hardness of a styrene copolymer elastomer sheet is 30 by the international rubber hardness prescribed | regulated by JISK6253-2: 2012.

(Evaluation method of puncture property (2))
The microneedle sheet prepared above was disposed on a styrene copolymer elastomer sheet as a model of the skin, and one end thereof was fixed to the styrene copolymer elastomer sheet (hereinafter, the fixed end is “fixed end ")). In the vicinity of the fixed end, a cylindrical rod (made of metal) having a diameter of 0.8 mm to 1.2 mm was disposed in the width direction of the microneedle sheet. The microneedle sheet is brought into close contact with the curved surface of the cylindrical rod and bent 180 °, and the axial center of the cylindrical rod is in contact with the styrene copolymer elastomer sheet side and the direction away from the fixed end of the microneedle sheet The microneedle sheet was drawn out and the microneedles were punctured into the styrene copolymer elastomer sheet. In addition, the hardness of a styrene copolymer elastomer sheet is 30 by the international rubber hardness prescribed | regulated by JISK6253-2: 2012.

The evaluation of the puncture property was performed by comprehensively evaluating these items after evaluating each item of 1) mobility of the bending portion, 2) easiness of bending, and 3) rewindability. Specifically, the following criteria were evaluated.
1) Mobility of Flexed Part The case where the sheet could not be drawn out smoothly while bending the sheet was evaluated as x, and the case where the sheet could be drawn out smoothly while bending the sheet was evaluated as ○.
2) Flexibility The case where the microneedle sheet could not be bent was evaluated as x, and the case where the microneedle sheet could be bent was evaluated as ○.
3) Rewindability After puncturing the microneedle with the styrene copolymer elastomer sheet, the case where the microneedle can hold a flat surface without being rewound from the styrene copolymer elastomer sheet is evaluated as ○, and the microneedle has a styrene co-weight The case where the sheet was slightly rewound from the united elastomer sheet, but could be held flat by pressing from above was evaluated as Δ, and the case where the microneedle was significantly rewound from the styrene copolymer elastomer sheet was evaluated as x.
4) Prickability In the evaluations of the above 1) to 3), the case where there was no x was evaluated as ○, and the other cases were evaluated as x.
The results are shown in Table 1.

The test pieces having a descent distance in the range of 4.5 cm to 12.9 cm were all excellent in the mobility of the fold, the easiness of bending, and the rewindability after puncturing, and exhibited excellent puncturing properties. In particular, in the test piece in which the descent distance is in the range of 6.2 cm to 12.9 cm, no rewinding was observed after puncturing, and particularly excellent punctility was exhibited. In addition, in the test piece whose descent | fall distance exceeds 12.9 cm, the microneedle buckled on a styrene copolymer elastomer sheet, and the tendency for it to be hard to be punctured by a styrene copolymer elastomer sheet was recognized.

[Test Example 2: Measurement of Descending Distance ]
(Preparation of microneedle sheet)
For three metal foils (SUS 304, SUS 316 L, and titanium) of three different types of material having thicknesses of 10 μm, 20 μm and 50 μm, the following two patterns of microneedles with different arrangement densities:
D94 (length: 500 μm, width: 220 μm, placement density: 100 pcs / cm ² )
D96 (length: 500 μm, width: 220 μm, placement density: 75 pcs / cm ² )
Various microneedle sheets were produced by etching to obtain

( Descent distance test)
The descent distance was measured in the same manner as in Test Example 1. The results are shown in Table 2.

The appropriate descent distance was shown for any of the materials.

  10 microneedle sheet 11 main surface 12 microneedle

Claims (1)

A plurality of microneedles formed on the sheet substantially along the main surface of the sheet;
In accordance with the slide method specified in JIS L 1096: 2010, after the upper surfaces of the slide type tester body and the movable table are matched, the 5 mm × 150 mm sheet is placed, and the end of the sheet Fixing 2 cm with a weight, gently turn the handle to lower the carriage, and when the free end of the sheet moves away from the carriage, the lowering distance of the sheet measured is 6.2 cm to 12.9 cm. ,
Material of the sheet is titanium or a titanium alloy,
The thickness of the sheet is 5 μm to 50 μm,
The microneedles stand up from the main surface by bending the sheet,
Micro needle sheet.

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